Nu-nitroso-nu-(2-hydroxyethyl) urea



United States Patent C) 3,267,138 N-NITRO50-N-(2-HYDROXYETHYL)UREAJean-Louis Pomot, Neuilly-sur-Seine, France, assignor to The NorwichPharmacal Company No Drawing. Original application June 20, 1963, Ser.

No. 289,383, now Patent No. 3,215,701, dated Nov. 2,

1965. Divided and this application May 18, 1965, Ser.

1 Claim. (Cl. 260-553) This application is a division of applicationSerial No. 289,383, filed June 20, 1963, and now Patent No. 3,2l5,- 701.

The present invention relates to a new process for the preparation of3-amino-2-oxazolido-ne hydrochloride. There is great interest in thesalts of 3-amino-2-oxazolidone for their use in a reaction withaldehydes or ketones, to obtain hydrazone-s corresponding to the generalformula:

R HzC CH2 in which R and R represent, either an atom of hydrogen or analkyl group, substituted or not, or an isocyclic group, substituted ornot, or a heterocyclic nucleus, substituted or not.

3-amino-2-oxazolidone hydrochloride may be used especially in themanufacture of certain compounds known for their therapeutic propertiessuch as (S-nitrofurylidone)-3-amino-2-oxazolidone, by reaction withS-nitroiurfural or with its diacetate.

The present invention has been conceived, notably, in order to procurecheaply an aqueous acid solution of 3- amino-Z-oxazolidone hydrochloridewhich may be utilized as an intermediate in a variety of chemicalsynthesis.

It has been conceived, particularly, with the view of the possibility ofobtaining such a solution in several stages carried out successivelywith the same apparatus, without isolation of intermediary products.

This invention provides a short, new, economical process for thepreparation of 3-amino-2-oxazolidone hydrochloride which comprises (a)Heating a mixture of monoetha-nolamine and urea,

(b) Cooling and nitrosating,

(c) Heating to liberate nitrogen,

(d) Cooling and nitrosating,

(e) Cooling and reducing,

(f) Filtering to obtain said 3-amino-2-oxazolidone hydrochloride.

Additionally, and in the course of this process a new compound,N-nitrosohydroxyethyl urea is porduced and can be isolated by theprocess which comprises (a) Heating a mixture of monoethanolamine andurea,

('b) Cooling and nitrosating, and

(c) Isolating said N-nitrosohydroxyethyl urea.

According to a particularity of the invention, the process comprehendsthe reduction of 3-nitroso-2-oxazolidone by means of zinc andhydrochloric acid with a high induction of heat to obtain a high yieldof 3-amino-2-oxazolidone hydrochloride in aqueous solution.

Another specialty of the invention lies in the preparation of an aqueoussolution of 3-nitroso-2-oxazolidone containing, in advance, the amountof hydrochloric acid required for reduction to the amino compound, bytwo successive nitrosations of beta-hydroxy ethyl urea with intermediarydenitrosating cyclization, whereby an aqueous acid solution of 3a-mino-2-oxaz-olidone hydrochloride may be prepared directly from thisurea using the same apparatus without isolation of the intermediaryproduct.

In the preferred practice of this invention, it is desirable, in orderto obtain the best yield, to use the minimum quantity of water fordissolution of the sodium nitrite used during the first nitrosation;this amount may be about two times the weight of the beta-hydroxy ethylurea. For the same reason it is preferable to use industrial sodiumnitrite in excess in relation to the quantity required in order to fix anitro group on a molecule of beta-hydroxy ethyl urea. A convenientexcess is about 10% in proportion to the stoichiometric quantity.

There is an advantage in preparing, from the very first, such an aqueoussolution of sodium nitrite and of betahydroxy ethyl urea and ofgradually introducing it afterward into the concentrated hydrochloricacid in order to produce a nitrosation according to the equationHO-CH2-OH2NHOONH2 NOzNa H'Ol The nitroso beta-hydroxy ethyl urea (I) isvery unstable and decomposes rapidly, as soon as its aqueous solutionreaches a temperature above 20 C., to yield the oxazolidone, bydenitrosation beginning with nitrogen:

1120 i O NE In every way, it is possible and advantageous to proceed sothat the first stage of the process, leads at once to the production ofa solution of oxazolidone, drawing partly on the exothermic character ofthe reaction. One may, particularly, gradually introduce the aqueoussolution of sodium nitrite and of beta-hydroxy ethyl urea into theconcentrated hydrochloric acid at a temperature of 0 to 15, moreparticularly at about 10, so that the nitrosation is carried out at alow temperature, and allow the temperature to raise spontaneously inproportion to the addition of the solution, then as the case requires,heat to at least 35; the final temperature may be from 35 to 50 C., moreespecially around 40 C.; it is maintained until the cessation of theliberation of nitrogen.

The amount of hydrochloric acid employed is, preferably, calculated sothat the acid assures the initial nitrosation, the nitrosation of thecyclized product, that is to say the oxazolidone, the reduction of thenitroso oxazolidone and finally the acidity of the final mediumcontaining the amino oxazolidone. In practice, the weight of concentrated hydrochloric acid, calculated on an acid with a density of 1.19,must be at least eight times, more particularly about ten times, that ofthe beta-hydroxy ethyl urea used. The amount of acid used is not limitedabove that dictated by economi considerations.

Once the nitrogen is liberated, the solution of ox-azolidone is cooledfor a further nitrosation. It sufiices to take the temperature down toC., but a lower temperature, for example between 0 and 15 C., islikewise convenient. Sodium nitrite is then gradually added, in anamount approximately equal to the preceding quantity, in solution in theminimum of water capable of dissolving it, probably about one to twotimes, particularly about 1.5 times, the weight of the nitrite. It issuitable to regulate the rate of addition so that the temperature is notraised above C.

According to the equation N-nitroso oxazolidone (IV) is obtained in thedissolved state. The solution likewise contains some sodium chloridefrom the two successive nitrosations and a sufficient quantity ofhydrochloric acid to assure the reduction with zinc in the followingstage.

For this latter, as was indicated above, it is of interest to carry outthe reduction very rapidly, at a temperature as low as can be usedindustrially, for the yield is so much the better. In practice, itsufiices to cool the solution to about 20 C., it being understood that alower temperature may be used, and to add a sutficient quantity ofcrushed ice so that the temperature, during the reduction with zinc,does not exceed C. Then the zinc powder is added in excess, all at once,this excess being 10 to 40% in proportion to the theoretical quantity,preferably from 15 to When the reduction is completed and the liberationof the hydrogen has ceased entirely, the mass is filtered to separatethe solid impurities carried over from the zinc powder.

The solution thus obtained contains, besides 3-amino- 2-oxazolidonehydrochloride, some sodium chloride, some zinc chloride and hydrochloricacid. It may be used, such as it is, or after neutralization withhydrochloric acid by sodium acetate, for the preparation of hydrazonesby addition of aldehydes or ketones.

Beta-hydroxy ethyl urea may be prepared by application of one of theknown methods of alkyl-ation of urea:

(a) By heating equimolecular quantities of rnono ethanolamine and ureafor 4 hours at a temperature between 110 and 115 C. The beta-hydroxyethyl urea thus obtained may be utilized in the crude state withoutfinal purification by crystallization.

(:b) By boiling an aqueous solution of mono-ethanolamine hydrochloridewith an excess of urea. The solutions of beta-hydroxy ethyl ureaobtained, which contain equally an excess of urea and of ammoniumchloride, may be used as such for nitrosation.

(c) By reaction of potassium cyanate or of sodium cyanate upon asolution of mono-ethanolamine hydrochloride. The solution ofbeta-hydroxy ethyl urea obtained which contains likewise some potassiumchloride or sodium chloride, may be utilized for the nitrosation.

The example below is given by way of illustrating, but not limiting, theinvention:

4 Example A mixture of Grams Mono-ethanolamine 12 Urea 12 was heated for4 hours at a temperature between 110 and 115 C.

The mass was cooled to C. and 35 grams of water were added. To thissolution 16 grams of sodium nitritesolution Iwere added.

In a balloon flask equipped with a stirrer, a thermometer and a droppingtunnel, placed in an ice bath, 230 ml. of concentrated hydrochloric acidof a density of 1.19 was introduced, and this was cooled while stirringto a temperature of +10 C.

Solution I was poured into the funnel and little by little added to thecold hydrochloric acid, the rate of inlet being regulated so that thetemperature rapidly attains 25 C. and is maintained there.

When all of solution I had been added, the mass was reheated to 40 C.and this temperature was maintained until all the gases had ceased tobeliberated.

Again the contents of the balloon flask were cooled by mixture of iceand salt until the temperature of the liquid reached 5 C. Then solutionII, which had been prepared by dissolving 16 grams of sodium nitrite in25 grams of water, was introduced into the funnel.

Solution II was added progressively as the mass was stirred, so that thetemperature remained lower than 10 C.

After the addition of solution II, the mass was cooled to 20 C. and 200grams of crushed ice was added. Then, all at once, 30 grams of zincpowder, passing through a 300 sieve, were poured in. The reaction wasviolent and the temperature rapidly increased to 10-15 C. The solutionwas stirred 30 minutes longer and filtered in order to separate thesolid impurities coming from the zinc.

The resultant solution was of a volume of about 500 cc. and contained:

Grams 3-amino-2-oxazolidone (in the form of hydrochloride) 8.6 Sodiumchloride 27 Zinc chloride 62.5

This solution, which contains, an excess of hydrochloric acid, may beused directly to prepare N-S-nitrofurfuryL idene-3amino-2-oxazolidone bythe following method, for example:

20 ml. of an aqueous solution of formaldehyde (40%) and 21 grams ofcrystalline S-nitrofurfural diacetate were added to the resultantsolution of the example. The mass was brought to 80 C. while stirringand this temperature was maintained for 30 minutes. The appearance of ayellow coloration was observed, thenN-S-nitrofurfurylidene-3amino-2-oxazolidone began to precipitate in theform of bright yellow crystals. After standing overnight, the crystalswere separated by filtration, washed with water and dried at C. 20 gramsof practically pure N-(S-nitrofurfurylidene)3amino-2-oxazolidone wasobtained.

What I claim is:

The compound N-nitroso-N- 2-hydroxyethyl) urea References Cited by theExaminer UNITED STATES PATENTS 2,253,528 8/1941 Olin 260-553 2,683,6967/1954 Muller et a1. 260553 HENRY R. JILES, Primary Examiner.

JAMES A- TURNIBSEED, Assistant Examiner.

